Constituents of Withania Somnifera Dun. Part X The Structure of Withanolide D

Withanolide D, the major component of the leaves of Withania somnifera chemotype II, is a steroidal lactone of the withanolide type, isomeric with withaferin A. It has been identified as 5, 6β-epoxy-4β, 20α-dihydroxy-1-oxo-(5β)witha-2, 24-dienolide. The structure has been elucidated by NMR measurements and by chemical degradation to 4β-acetoxy-5,6β-epoxy (5β) pregnan-1, 20-dione.     

Intermediates of Prostanoid Synthesis. Stereospecific conversion of (+)-5β-hydroxycyclopenten-2-yl-1β-acetic acid γ-lactone into (+)-1β-methoxycarbonylmethyl-2β,3β-(p-nitrobenzylidene)-dioxycyclopentan-5-one

Starting from (+)-5β-hydroxycyclopenten-2-yl-1β-acetic acid γ-lactone ( 1 ), (+)-1β-methoxycarbonylmethyl-2β, 3β-(p-nitrobenzylidene)-dioxycyclopentan-5-one ( 7 ) was prepared within 4 steps. Subsequent cleavage of the latter gives (−)-3β-hydroxy-1-methoxy-carbonylmethylcyclopent-1-en-5-one ( 8a ). Hydroxylation of the lactone ( 1 ) was found to give (+)-2β,3β,5β-trihydroxycyclopentyl-1β-acetic acid γ-lactone ( 2a ) with cis-oriented hydroxy groups in respect to the lactone ring. No formation of the trans-isomer, as has been reported earlier [4], was observed.     

LINK Synthesis with 3-Hydroxy-1H-pyrazoles: 3-Carboxyisoalkyloxy-1H-pyrazoles – bicyclic acylpyrazolium salts and γ-Lactams – 3-Carboxyisoalkyloxy-4,5-dihydro-1H-pyrazol-5-ones

1-Substituted 3-hydroxy-1H-pyrazoles 1 react with chloroform, NaOH, and aceton resp. butan-2-one O-regiospecifically to yield 2-methyl-2-[(1H-pyrazol-3-yl)oxy]-propanoic resp. -butanoic acids 14 via a dichlorocarbene ( 12 )–dichlorooxirane ( 9 ) pathway. Chlorides 17 of 14 easily cyclize to N-acylpyrazolium salts 18/19 , which quantitatively afford esters 22–26 and amides 27–29 of 14 . Enantiomers of the butanoic acid 14th , obtained via their diastereomeric cholesterol esters, differ in their stimulus to peroxisome proliferation. At 140 °C pyrazolium salts 18 undergo thermolysis to bicyclic β-oxa-γ-lactams 30–32 . 3-Carboxyisoalkylamino-pyrazoles similarly give 1H-β-aza-γ-lactams 34 . Reactions of 14 with surplus SOCl₂ result in 6-chloro- 37 resp. 7-chloro-β-oxa-γ-lactams 38 via chlorosulfinylation and extrusion of SO, and in 4,4-bispyrazolyl-sulfoxide 39 . A mild introduction of additional O-functions into pyrazoles affording 4,5-dihydro-3-hydroxy-5-oxo-1H-pyrazoles 52–57 is presented. Biological effects of the new pyrazoles are protection against shock and ADP-induced thromboembolism, reduction of serum lipids and improvement of blood flow.     

Untersuchungen zur Bromierung/Dehydrobromierung von 17α-Cyanmethyl-17β-hydroxy-östr-5(10)-en-3-on

Investigations on the Bromination/Dehydrobromination of 17α-Cyanomethyl-17β-hydroxy-estr-5(10)-en-3-one Bromination/dehydrobromination of 17α-Cyanomethyl-17β-hydroxy-estr-5(10)-en-3-one 1a in the presence of pyridine leads to 17α-cyanomethyl-17β-hydroxy-estra-4, 9-dien-3-one 2a . The reaction was studied in various solvents with several bromination agents. Intermediates and byproducts of the reaction were isolated and their structures elucidated.     

Partialsynthesen von Cardenoliden und Cardenolid-Analogen. I. α,β- und β,γ-ungesättigte Lactonring-methylierte Cardenolide

Partial Syntheses of Cardenolides and Cardenolide Analogues. I. α,β- and β,γ-Unsaturated Lactone Ring-Methylated Cardenolides Base-catalyzed methylation of digitoxigenin 1a with methyl iodide and sodium hydride in DMF leads to the α,β-unsaturated cardenolides 2–5 and, after rearrangement of the CC-double bond, to the β,γ-unsaturated cardenolides 6 and 7 . Opening of the lactone ring results in the formation of 8 . Allylic oxidation of 4b affords the 14,21-epoxide 10 . Only the 22-methyl derivative 4a and its 3-O-tridigitoxoside 4d show strong biological effectivity, whereas methylation at 21R- or 21S-position results in considerable loss in activity.     

屈螺酮关键中间体的合成研究

以NBS为溴源,3-特戊酰氧基-5β,6β-环氧-7β-羟基-15β,16β-二亚甲基-孕甾-17-酮为原料,在三苯基膦催化剂的作用下合成了屈螺酮的关键中间体3-特戊酰氧基-5β,6β-环氧-7α-溴-15β,16β-二亚甲基-孕甾-17-酮,考察了NBS的用量、催化剂的用量、反应温度、反应时间对3-特戊酰氧基-5β,6β-环氧-7α-溴-15β,16β-二亚甲基-孕甾-17-酮收率的影响。实验结果表明,最佳投料条件下目标物的质量收率为89.5%。该方法条件温和,操作简单,易于实现工业化生产。     

Studies of B-ring aromatic tetracyclic Triterpenoid Derivatives

By treatment of methyl 3β-acetoxy-7β-hydroxy-4,4,14-trimethyl-1-oxo-5α-chol-8-en-24-oate 3 with p-toluenesulfonyl chloride in pyridine methyl 3β-acetoxy-4,4,14-trimethyl-11-oxo 19-norchola-5,7,9-trien-24-oate 1a was synthesized and its structure confirmed by spectral evidence. From 3β-acetoxy-19-norlanosta-5,7,9-trien-11-one 1b the 7-amino derivative 1d , of which was prepared by nitration and selective catalytic hydrogenation (10% Pd/C) of the obtained 7-nitro compound 1c .     

13C-NMR-Spektroskopie von bromierten 3-Keto- und 3β-Acetoxy-5α-cholestan-Verbindungen

¹³C-NMR Spectroscopic Investigations of Brominated 3-Keto- and 3β-Acetoxy-5α-cholestane Derivatives The chemical shifts of some brominated 3-keto- and 3β-acetoxy-5α-cholestane derivatives are determined. The substituent effects of bromine atoms on chemical shifts (SCS) and their additive behaviour, especially γ-SCS, are discussed.     

Partialsynthesen von Cardenoliden und Cardenolid-Analogen. VI. (20R)- und (20S)-Cardanolide

Partial Syntheses of Cardenolides and Cardenolide Analogues. VI. (20R)- and (20S)-Cardanolides (20R)-Dihydrodigitoxigenin ( 2 ) and (20S)-dihydrodigitoxigenin ( 4 ) as well as their 3-acetates 3 and 5 , respectively, were synthesized by catalytic hydrogenation of the appropriate cardenolides and separation by column chromatography on silica of the mixtures of stereoisomers. Hydroxymethylation of 3 and 5 followed by selective elimination yielded (20S)- and (20R)-14-hydroxy-22-methylene-5β,14β-cardanolide 3-acetate ( 10 and 16 ), respectively. The biological activities of the synthesized 20-stereoisomeric cardanolides are investigated and discussed. Cardanolides 10 and 16 have a strong inhibitory activity on the proliferation of Ehrlich ascites carcinoma cells in suspension culture.     

Neue Produkte durch Ringerweiterungen von festen 17-Hydroxy-20-ketosteroiden mit gasförmigem Chlorwasserstoff

New Products by Ring Expansions of Solid 17-Hydroxy-20-ketosteroids with Gaseous Hydrochloric Acid Gaseous hydrogen chloride reacts directly with crystalline 17-hydroxy-20-ketosteroids like 17α-hydroxy-progesterones ( 1, 5, 6, 8 ) to give enlargement of ring D. In addition to the known acyloine rearrangement, new reaction types are observed which give rise to the products of substitutive rearrangement with elimination of water, 16β-Chloro-( 3 ) and 16α-chloro-16β-methyl-17-oxo-D-homosteroids ( 7, 9 ) are formed stereoselectively. The drying agent magnesium sulfate may keep the reaction products solid. Mechanistic proof is provided spectroscopically (IR) and by the isolation of 17aβ-hydroxy-17aα-methyl-D-homoandrost-4-ene-3,17-dione ( 2 ) and its conversion to 16β-chloro-17aβ-methyl-D-homoandrost-4-ene-3,17-dione ( 3 ) with gaseous hydrogen chloride. The new reaction types do not occur in solution.     

Steroide. XLVI. Darstellung von 15.16.17-trisubstituierten Steroiden durch Ringöffnung von 17β-substituierten 15β.16β-Epoxy-östra-1.3.5(10)-trien-3-methyläthern

Steroids. XLVI. Preparation of 15,16,17-Trisubstituted Steroids by Ring Cleavage of 17β-Substituted 15β,16β-Epoxy-estra-1,3,5(10)-triene 3-Methylethers The ring cleavage of 15β.16β-epoxy-3-methoxy-estra-1-3,5(10)-triene-17β-ol 1a with strong nucleophiles occurs mainly at C-16, yielding 16α-substituted 15β,17β-diols 2a–f . Besides this, 1a is cleaved to a small extent at C-15, yielding the 15α-substituted 16β,17β-diols 3a—f and the Δ¹⁴-16,17β-diol 5a . The structures have been elucidated by means of i.r., H-n.m.r. and mass spectroscopy.     

A convenient one step synthesis of 2,4-dialkyl-2-hydroxy-alkyl-γ-butyrolactone using lithium naphthalenide

One mole of propionic acid ( I ) reacts with 2 mol of 1,2-butylene oxide ( II ) in the presence of lithium naphthalenide to give 4-hydroxy-2-(2′-hydroxybutyl)-2-methylhexanoic acid ( V ), which can be easily converted into 2-(2′-hydroxybutyl)-2-methyl-4-ethyl-γ-butyrolactone ( VII ). Similarly, 2,4-dialkyl- and 2,4,4-trialkyl-2-hydroxyalkyl-γ-butyrolactones were prepared from other carboxylic acids having two hydrogens at 2-position and various epoxides.     

Synthese und Reaktionen von β-Campholenverbindungen

Synthesis and Reactions of β-Campholene Compounds In contrast to the well known α-campholenic ( B ) and fencholenic compounds ( C ) little is known about β-campholenic derivatives ( A ) because of their difficult accessibilitiy. β-Campholenic compounds ( A ) can be obtained: (1) by Baeyer-Villiger oxidation of camphor via lactone 7 and β-dihydrocampholenic lactone ( 5 ); (2) by Beckmann fragmentation of camphor oxime via α-( 2 ) and β-campholenic nitril ( 3 ) and the lactone 5 ; and ( 3 ) by acid catalysed rearrangement of α-campholenic derivatives ( B , 17a , b ). The β-analogous brahmanol ( 14 ) can be synthesized by the reaction of the β-campholenic bromide ( 11 ) with methyl diethyl malonate or by rearrangement of brahmanol.     

Synthesen von β-Fur-2-yl-α-halogenacrylonitrilen

Syntheses of β-Fur-2-yl-α-halogenacrylonitriles Syntheses of β-fur-2-yl-α-halogenacrylonitriles 2a–f by Wittig-olefination of furfurales, Hunsdiecker-reaction of β-(5-nitro-fur-2-yl)-α-cyanoacrylic acid 3 , halogenation of β-fur-2-yl acrylonitriles and reaction of furfurales with β-azido-α-halogen-γ-methoxy-Δ^α,β-crotonolactones 9 are described.     

Umsetzung von Bromderivaten des 6β-Bromcholest-4-en-3-ons mit NaBH4 und 13C-NMR-spektroskopische Charakterisierung der Reduktionsprodukte

Reaction of Bromo Derivatives of 6β-Bromocholest-4-en-3-one with NaBH₄ and ¹³C-NMR Spectroscopic Characterization of the Reduction Products Bromo derivatives of 6β-bromcholest-4-en-3-one ( 1a–f ) were reduced with sodium borohydride. The main product of the reduction of 2α,6β-dibromcholest-4-en-3-one ( 1b ) was 2α-bromocholesterol ( 2b ). In other cases the corresponding derivatives of 6β-bromocholest-4-en-3β-ol ( 3a ) were formed. The chemical shifts of all new products were determined. They confirmed the structure of these new compounds.     

Herstellung und Charakterisierung der Sulfamate von Estra-3,17ξ-diolen. Schnelle Umsetzung von 16α-Fluorestradiol zum 16α-Fluorestradiol-3,17β-disulfamat

Estradiols are able to form two monosulphamates and one disulphamate. In the present work all the sulphamates of 17α-estradiol, 17β-estradiol and 16α-fluoroestradiol were synthesized and characterized. For characterization NMR spectroscopy was used first of all. Because of its high sulphatase inhibitory efficiency 16α-fluoroestradiol-3,17β-disulphamate found a special interest among the new sulphamates. Just the binding between sulphamate and sulphatase favoured 16α-[^18F]fluorestradiol-3,17β-disulphamate to a new radio-pharmaceutical which should be appropriate to image the active sites of sulphatase by positron emission tomography. The preparation of 16α-[¹⁸F]fluoro-estradiol-3,17β-disulphamate requires a simple and rapid procedure. The conditions for such a procedure were also elaborated using non-radioactive substances.     

Synthese und Strukturaufklärung von 19-Nor-pregnanderivaten mit stickstoffhaltigen Vierringen in 14,15-Stellung

Synthesis and Structural Elucidation of 19-Nor-pregnane Derivatives with Nitrogen-Containing Four-Membered Rings in 14,15-Position The introduction of a C₂ side chain in the 17-position of 3-methoxy-14β, 15β-(3′,4′-azetidine)-estra-1,3,5(10)-trien-17β-ol ( 1 ) is described. Hydroboration of the 17-ethylidene compound 4 gives a mixture of the 17αH and 17α-pregnane derivatives 6 and 6a in 70% and 10% yields, respectively. Birch reaction of 6 , followed by oxidation yields the 14β,15β-(3′,4′-azetidine)-19-nor-pregn-4-ene-3,20-dione ( 12 ). The new compounds were characterized by ¹H-n.m.r. The structure of product 13 was determined by X-ray crystallography.     

Synthese,Reaktivität und 1H-NMR-Daten von 14,15-Methylenderivaten der Androstan- und Östratrienreihe

Synthesis, Reactivity and ¹H-NMR-Spectroscopy of 14,15-Methylene Derivatives of the Androstane and Estratriene Series Under the activating and syn-directing effect of the 17-hydroxy group the Simmons Smith cyclopropanation of 14,15-unsaturated 17-hydroxy steroids of the androstane and estratriene series 1a, 5 and 9 affords the 14,15-methylene steroids 2a, 6 and 10 with cis position of the 14,15-methylene and 17-hydroxy groups in a stereospecific reaction. Oxidation of these compounds yields the 17-keto derivatives 3, 7 and 11 , which were reduced to the compounds 4a, 8 and 12 with trans position of the 14,15-methylene and 17-hydroxy groups by complex hydrides or diborane. In a phase transfer catalyzed reaction dichloro- or dibromocarbene was added to 3β, 17β-diacetoxy-5α-androst-14-ene 1b forming the 14β, 15β-dihalogenmethylene steroids 13 and 14 . The 17-keto steroids 7 and 11 were transformed into 17-methyl and 17-ethynyl derivatives 15–20 . Cleavage of the cyclopropane ring of 2a, 2b and 3 by catalytic hydrogenation affords the 14β-methyl derivatives 21–23 , the acid catalyzed ring opening with hydrogen chloride yields the 14β-chloro, 15β-methyl derivatives 24–29 . Structure elucidation has been established by ¹H n.m.r. and mass spectroscopy. The configuration at C17, C14 and C15 was also determined by means of ¹H n.m.r. spectroscopy, using the chemical shifts of the 18-protons, the coupling constants and the chemical shifts of the 17-protons. The configuration of the 17-disubstituted steroids was established with the aid of an europium shift reagent.     

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.     

α-Arylamino-cyanomethylen-pyrazolinone aus Azomethinfarbstoffen und Malonsäuredinitril

α-Arylamino-cyanomethylene-pyrazolinones from Azomethine Dyes and Malonodinitrile The reaction of azomethine dyes ( 1a–g ) with malonodinitrile ( 2 ) gives dicyanomethylene-pyrazolin-5-one ( 4 ) which immediately reacts with the eliminated anilines by HCN-amine exchange giving the deeply coloured arylamino-cyanomethylene-pyrazolinones ( 5a–g ). Structural investigations and a study of the absorption characteristic are described.